In human populations cryptorchidism occurs in 3-4% of males at birth, making this abnormality the most frequent congenital birth defect in newborn boys. Two main consequences of an abnormal location of the testis are infertility caused by degeneration of the spermatogonial cells and a high risk of malignant tumors in adulthood. Testicular descent during development is a complex, multistage process whereby the male gonads progress toward the scrotum. Failure in any stage of this process results in cryptorchidism or undescended testis. The long-term objectives of this proposal are to identify key genetic components that control the molecular mechanisms of the early phases of testicular descent. A new mouse mutation, crsp (cryptorchidism with spotting), discovered in Baylor College of Medicine, will be used as a model system to study this problem. Male mice homozygous for crsp have a high intraabdominal position of the testes, associated with complete arrest of spermatogenesis in the early stages of proliferation. Preliminary data has shown that the mutation does not specifically affect spermatogenesis but testicular descent during development. It is caused by a transgene insertion into the telomeric region of mouse chromosome 5 producing a deletion of the chromosomal DNA. The PI has cloned the critical genomic region into a series of overlapping BAC clones and estimated the physical distance of the deletion. The present application is designed to test the hypothesis that the crsp mutation disrupts one of the early determinants to testicular descent and that malfunction of the crsp gene could be responsible for the cryptorchidism in mutant. The specific aims are: 1) to characterize the molecular-genetic rearrangements in the mutant mice; 2) to identify genes residing within the critical region; 3) to evaluate potential candidate genes in mouse by BAC transgenic rescue and generation of gene-deficient mutants; 4) to identify and characterize the human CRSP gene. The resulting information will provide a framework for elucidating the function of the CRSP gene in the etiology of cryptorchidism, determination of the CRSP developmental pathways relevant to the human disorder and development of new diagnostic tools and future therapeutic routes for this most common birth defect in men.